The aberrant regulatory mechanism of glutamate transmission on N-methyl-D-aspartic acid (NMDA) receptor has been reported as one of the neuropathology in schizophrenia. The receptor is a heterotetramer composed of two structure subunits of NMDA receptor 1 (NR1) and NR2. The extracellular domain of these two subunits were responsible for modulatory and ligand binding functions, where the NR1 binds the co-agonist glycine, and the NR2 binds the neurotransmitter glutamate. The membrane channel domain is responsible for the entrance of calcium ions. The receptor requires the binding of glutamate from NR2 subunit to activate the receptor, and requires the co-agonist of glycine binding for the efficient opening of the ion channel. Modulation the glycine binding site of NMDA receptor may improve the cognitive function and negative symptoms in schizophrenia. D-amino acid oxidase (DAAO) was found to be involved in the activation process of the NMDA receptor. The substrates of DAAO, especially the D-serine, may bind to the glycine site of the NMDA receptor as a co-agonist. This in turn may regulate the NMDA receptor in opening its calcium channel. D-serine has been found to inhibit the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated current in rat hippocampus neurons (Gong, X. Q. et al., Canadian Journal of Physiology and Pharmacology 2007, 85 (5), 546-55). Thus, DAAO was hypothesized to be implicated in the pathogenesis of schizophrenia. As the NMDA receptor also involved in affective disorder (Kaster, M. P. et al., Pharmacological reports: PR 2012, 64 (3), 706-13), it is likely that inhibiting the DAAO may elevate the function of NMDA and improve both the symptoms of schizophrenia and depression affective disorder (Hashimoto, K. et al., European Archives of Psychiatry and Clinical Neuroscience 2013).
Schizophrenia is a devastating mental disorder that afflicts approximately 1 percent of the worldwide population. The direct and indirect costs associated with this disorder make it extremely expensive (Abbott A. Nature, 2010; 468: 158-9). Clinically, schizophrenia is mainly characterized by positive symptoms, including delusions and hallucinations, negative symptoms, such as blunted emotions, anhedonia, and social isolation, and cognitive deficits such as the impairment of executive function, attention, and working memory. The initial and most common hypothesis regarding pathophysiology of schizophrenia originated from the antipsychotic treatments is dopamine hypothesis, especially for the treatment of positive symptoms (Howes, O. D; Kapur, S. Bulletin, 2009, 35(3), 549-62; Madras, B. K, Journal of the History of the Neurosciences, 2013, 22(1), 62-78). In contrast to positive symptoms, negative symptoms and cognitive deficits have not garnered considerable attention until recently. Unfortunately, the available antipsychotic medications are relatively ineffective at improving negative symptoms and cognitive deficits as well. After the initial discovery of antipsychotics for more than a half century, the field finds itself in need not only of alternative medications but also alternative targets, especially for negative and cognitive symptoms (Abbott A. Nature, 2010; 468: 158-9).
As a starting point from a neurotransmitter-based theory, hypofunction of N-methyl-D-aspartate receptor (NMDAR)-mediated signaling pathways has been cumulatively implicated in the associated learning, social impairments, long-term potentiation, and various types of learning and memory (Riedel G, Platt B, Micheau Behavioural Brain Res. 2003; 140:1-47). The involvement of the NMDAR system in schizophrenia is evidenced by the observations that NMDAR antagonists (i.e., phencyclidine (PCP) and ketamine) induced negative symptoms and cognitive dysfunction similar to that of schizophrenia, suggesting NMDAR may be particular relevant to persistent, poor-outcome forms of schizophrenia (Moghaddam B, Javitt D. Neuropsychopharmacology, 2012; 37: 4-15). Although the effect of glutamatergic dysfunction on the etiology of schizophrenia remains unclear, accumulating studies also suggest that dysregulation of glutamatergic neurotransmission may be involved in the pathophysiology of schizophrenia (Goff D C, Coyle J T. Am J Psychiatry, 2001; 158: 1367-77; Moghaddam B. Neuron, 2003; 40: 881-4; Lin C H, Lane H Y, Tsai G E. Pharmacol Biochem Behav, 2012; 100: 665-77). In the simplest version of the NMDAR models, the primary goal of treatment would be the restoration of function at the NMDAR itself or other targets beyond the NMDAR (Moghaddam B, Javitt D. Neuropsychopharmacology, 2012; 37: 4-15). Thus, the hypo-function of glutamatergic transmission in schizophrenic patients is a potential target of treatment and the drugs that enhance NMDARs function have been thought as the potential therapy (Lin C H, Lane H Y, Tsai G E. Pharmacol Biochem Behav, 2012; 100: 665-77). NMDARs are heteromeric complexes that contain NR1, NR2, and NR3 subunits. NMDARs also contain a glutamate recognition site in the NR2 subunit and a glycine modulatory site in the NR1 subunit. Both glutamate and glycine are agonists of the NMDARs (Clements J D, Westbrook G L. Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-d-aspartate receptor. Neuron, 1991; 7: 605-613). Since direct stimulation of the glutamate-binding site of NMDARs can produce excitotoxic neuronal death, the enhancement of NMDAR function by targeting glycine site or D-serine site of NMDAR may be more beneficial. One promising target is D-amino acid oxidase (DAO, DAAO) which is a flavoenzyme that metabolises D-serine, a co-agonist of the endogenous NMDAR. As such, it has the potential to modulate NMDAR function and to contribute to the widely hypothesized involvement of NMDAR signalling in schizophrenia. On the same vein, accumulating data from three lines of evidence support for this possibility (L Verrall, P W J Burnet, J F Betts, and P J Harrison, Mol Psychiatry. 2010 February; 15(2): 122-137). (1) DAO shows genetic associations to the disorder in several but not all studies; (2) the expression and activity of DAO are increased in schizophrenia; and (3) the inactivation of DAO resulted in behavioral and biochemical effects in rodents, suggesting potential therapeutic benefits. Because NMDAR dysfunction is considered to be involved in the positive, negative and cognitive symptoms of schizophrenia, there has been much interest in developing potent and selective DAO inhibitors for the treatment of negative and cognitive symptoms of schizophrenia (Sean M Smith, Jason M Uslaner, and Peter H Hutson, Open Med Chem J. 2010; 4: 3-9).
It has been reported that NMDA receptor enhancer has the following indications: (i) treatment for all symptom domains of schizophrenia and schizoaffective disorder, including negative, cognitive, depressive, positive and general psychopathology symptom domains (Tsai, G. E. and P. Y. Lin, Curr Pharm Des, 2010. 16(5): p. 522-37; and Singh, S. P. and V. Singh, CNS Drugs, 2011. 25(10): p. 859-85); (ii) treatment for depression (Huang, C. C., et al., Biol Psychiatry, 2013. 74(10): p. 734-41); (iii) treatment for Parkinson's disease (Gelfin, E., et al., Int J Neuropsychopharmacol, 2012. 15(4): p. 543-9; (iv) treatment for Tourette Syndrome (Singer, H. S., C. Morris, and M. Grados, Med Hypotheses, 2010. 74(5): p. 862-7); (v) treatment for mild cognitive impairment (MCI) and Alzheimer disease (AD) (Lin, C. H., et al., Biol Psychiatry, 2014. 75(9): p. 678-85); (vi) treatment for Post-traumatic stress disorder (PTSD) (Heresco-Levy, U., et al., Int J Neuropsychopharmacol, 2009. 12(9): p. 1275-82; Difede, J., et al., Neuropsychopharmacology, 2014. 39(5): p. 1052-8); (vii) treatment for Obsessive-compulsive disorder (OCD) (Wu, P. L., et al., J Clin Psychopharmacol, 2011. 31(3): p. 369-74; and Wilhelm, S., et al., Am J Psychiatry, 2008. 165(3): p. 335-41; quiz 409); (viii) analgesics (Gong, N., et al., Neuropharmacology, 2012. 63(3): p. 460-8).
D-serine is a full agonist at the allosteric glycine binding site of the NMDA receptor, and was reported to improve negative, cognitive symptoms, and symptoms poorly addressed by the standard D2 antagonist in schizophrenia (Ferraris, D. V. et al., Current pharmaceutical design 2011, 17 (2), 103-11) and in depression (Hashimoto, K et al., European Archives of Psychiatry and Clinical Neuroscience 2013). Inhibition of DAAO can increase the brain D-serine level directly therefore can be potentially used for the schizophrenia therapy (Miyamoto, S. et al., Molecular psychiatry 2012, 17 (12), 1206-27; Sacchi, S. et al., Current pharmaceutical design 2012; Ono, K. et al., Journal of neural transmission (Vienna, Austria: 1996) 2009, 116 (10), 1335-47) and even further for affective disorder.
Known inhibitors of DAAO include benzoic acid, pyrrole-2-carboxylic acids, and indole-2-carboxylic acids. Indole derivatives and particularly certain indole-2-carboxylates have been described in the literature for treatment of neurodegenerative disease and neurotoxic injury. EP 396124 discloses indole-2-carboxylates and derivatives for treatment or management of neurotoxic injury resulting from a CNS disorder or traumatic event or in treatment or management of a neurodegenerative disease. U.S. Pat. Nos. 5,373,018; 5,374,649; 5,686,461; 5,962,496 and 6,100,289 disclose treatment of neurotoxic injury and neurodegenerative disease using indole derivatives. WO 03/039540 disclose DAAO inhibitors, including indole-2-carboxylic acids, and methods of enhancing learning, memory and cognition as well as methods for treating neurodegenerative disorders. Patent Application No. WO/2005/089753 discloses benzisoxazole analogs and methods of treating mental disorders, such as Schizophrenia. Recently, compounds such as the AS057278 (5-methylpyrazole-3-carboxylic acid) (Adage, T. et al., Eur Neuropsychopharmacol 2008, 18 (3), 200-14), CBIO (6-chlorobenzo[d]isoxazol-3-ol) (Ferraris, D. et al., J Med Chem 2008, 51 (12), 3357-9) and 4H-thieno[3,2-b] pyrrole-5-carboxylic acid from Merck (Smith, S. M. et al., J Pharmacol Exp Ther 2009, 328 (3), 921-30) have been reported to have DAAO inhibitory effect.
There is a need to develop candidate drugs having DAAO inhibitory effect to treat various neurological and physical disorder.